Over the past few years, we completed human trials of recombinant glycoprotein vaccines for treatment and prevention of genital herpes. The vaccines proved inadequate. We turned, therefore, to animal model studies using new classes of HSV vaccines to define ones that appear to be more immunogenic and potentially more effective. We are comparing recombinant glycoprotein vaccines with novel DNA-based and live, genetically-engineered vaccines for genital herpes. This has the theoretical advantage of inducing better cellular immune responses. The DNA vaccine expresses gD2 under a strong CMV promoter. The engineered virus vaccine termed dl5/29 was made by David Knipe at Harvard and consists of HSV-2 deleted for genes 5 and 29, impairing replication and establishment of latency. In mice and guinea pigs dl5-29 is as prtective as recombinant gD2 against acute disease, latency and recurrence rates. In guinea pigs, dl5-29 is more immunotherapeutic than recombinant protein in CFA/IFA. Over the past year, we developed techniques to recover and quantify from the spleen and regional sensory nerve ganglia CD8+ T cells that express interferon gamma upon exposure to HSV infected cells. We found that the dl5-29 vaccine induces signifcantly stronger specific T cell responses in the spleen and such cells traffic to and accumluate more rapidly and to higher total numbers in regional ganglia. Over the coming year we intend to characterize these t cells more fully and better define the roels they plauy in controlling primary and reactivaion infections.